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Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.

A personalised approach to the management of Medullary Thyroid Cancer (MTC) presents several challenges, however in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline RET testing in MEN 2 & 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. PET imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors which have shown improved progression free survival with better tolerability compared to outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients; from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.

Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. First, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PVs) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to the overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted toward such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information, personalized diagnostics and treatment is in close reach.

Context The significance of thyroid peroxidase (TPOAb) and thyroglobulin antibody (TgAb) in the pathogenesis of thyroid immune-related adverse events (irAEs) is unknown. Objective To characterize the association of anti-thyroid antibodies with the development of thyroid immune related adverse events. Methods A retrospective cohort study was conducted of patients with melanoma receiving immune checkpoint inhibitor (ICI) treatment. TPOAb, TgAb, and interleukin-6 (IL-6) were measured retrospectively using tumor-banked samples at baseline and at time of diagnosis of a thyroid irAE. In euthyroid patients (without thyroid irAEs) measures were repeated 30 to 60 days after ICI commencement, which was similar to the median time to onset of thyroid irAEs in other patients. Results A total of 122 patients were included—31 remained euthyroid, 47 developed subclinical thyrotoxicosis, 37 developed overt thyrotoxicosis, and 7 developed overt hypothyroidism without preceding thyrotoxicosis. Baseline elevation of TPOAb or TgAb was present in 19 (16%) and 28 (23%) patients, respectively. Positive TPOAb or TgAb at baseline was 97% and 100% specific for eventual development of a thyroid irAE, respectively. During ICI treatment, overt thyrotoxicosis, but not other subtypes of thyroid irAE, was associated with statistically significant increases in the titer of TgAb and TPOAb. Baseline IL-6 levels were not associated with thyroid irAE onset but statistically significantly increased during treatment in patients who developed overt hypothyroidism. Conclusions TPOAb and TgAb positivity at baseline was more prevalent in patients who developed thyroid irAEs. Statistically significant increases or new antibody positivity was observed in association with overt thyrotoxicosis. TPOAb and TgAb positivity or increases during ICI treatment may be a useful biomarker to identify patients at increased risk of thyroid irAEs, particularly overt thyrotoxicosis.

Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(−6 to +84). Synthetic pro[P1]PTH(−6 to +34) and pro[S1]PTH(−6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(−6 to +34), pro[P1]PTH(−6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(−6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.

Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs’s cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew’s Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

Background The 2015 American Thyroid Association (ATA) Guidelines permit thyroid lobectomy (TL) or total thyroidectomy in the management of low-risk papillary thyroid cancer (PTC). As definitive risk-stratification is only possible post-operatively, some patients may require completion thyroidectomy (CT) after final histopathological analysis. Methods A retrospective cohort study of patients undergoing surgery for low-risk PTC in a tertiary referral centre was undertaken. Consecutive adult patients treated from January 2013 to March 2021 were divided into two groups (pre- and post-publication of ATA Guidelines on 01/01/2016). Only those eligible for lobectomy under rule 35(B) of the ATA Guidelines were included: Bethesda V/VI cytology, 1–4 cm post-operative size and without pre-operative evidence of extrathyroidal extension or nodal metastases. We examined rates of TL, CT, local recurrence and surgical complications. Results There were 1488 primary surgical procedures performed for PTC on consecutive adult patients during the study period, of which 461 were eligible for TL. Mean tumour size (P = 0.20) and mean age (P = 0.78) were similar between time periods. The TL rate increased significantly from 4.5 to 18% in the post-publication period (P < 0.001). The proportion of TL patients requiring CT (43 vs 38%) was similar between groups (P = 1.0). There was no significant change in complications (P = 0.55) or local recurrence rates (P = 0.24). Conclusion The introduction of the 2015 ATA Guidelines resulted in a modest but significant increase in the rate of lobectomy for eligible PTC patients. In the post-publication period, 38% of patients who underwent TL ultimately required CT after complete pathological analysis.

PURPOSE The improved access and affordability of next generation sequencing has facilitated the clinical use of gene panel testing to test concurrently patients for multiple heritable hyperparathyroidism syndromes. However, there is little guidance as to which patients should be selected for gene panel testing and which genes should be included in such panels. In this review, we provide a practical approach to considering, interpreting and managing genetic testing for familial primary hyperparathyroidism (PHPT) syndromes and familial hypocalciuric hypercalcaemia (FHH) in patients with PTH-dependent hypercalcaemia. We discuss known genes implicated in PHPT and FHH, testing criteria and yields, pre-test counselling, laboratory considerations, and post-test management. METHODS In addition to reviewing the literature, we conducted audits of local genetic testing data to examine the real-world yield of genetic testing in patients with PTH-dependent hypercalcaemia. RESULTS Our local audits revealed a positive genetic testing rate of 15-26% in patients with suspected hyperparathyroidism syndromes. CONCLUSION Based on the particular testing criteria met, affected patients should be tested for variants in the genes currently implicated in PHPT (MEN1, CDC73, RET, CDKN1B, GCM2, CASR) and/or FHH (CASR, GNA11, AP2S1). Patients should be provided with pre- and post-test counselling, including consideration of potential implications for family members.

Concern regarding suboptimal cure rates has led to some endocrine surgery units abandoning focused parathyroidectomy for primary hyperparathyroidism in favor of open bilateral neck exploration or making intraoperative parathyroid hormone estimation mandatory in focused parathyroidectomy. This study explores whether focused parathyroidectomy for radiologically localized primary hyperparathyroidism without intraoperative parathyroid hormone is still a valid approach.Retrospective review of a tertiary referral endocrine surgery unit database. All parathyroidectomies for primary hyperparathyroidism over 6 years (2013-2019) were included. Lithium-induced hyperparathyroidism, reoperations, familial disease, and concurrent thyroid surgery were excluded. Characteristics and outcomes for focused parathyroidectomy and open bilateral neck exploration were compared by intention-to-treat and treatment delivered. Persistence and recurrence, conversions and complications were analyzed as endpoints.A total of 2,828 parathyroidectomies were performed and 2,421 analyzed. By intention to treat there were 1,409 focused parathyroidectomies and 1,012 open bilateral neck explorations. Focused parathyroidectomy patients were younger: 63 vs 66 years (P.01); however, gender (77%, 79% female), preoperative peak serum calcium (2.72, 2.70 mmol/L [P = .23]), and serum parathyroid hormone (11.5, 11.0 pmol/L [P = .52]) did not differ. In total, 229 (16.3%) focused parathyroidectomies were converted to open bilateral neck exploration. Multiple gland disease was confirmed in 54.5% of converted patients. Median follow-up was 41 months (3-60 months). Persistence or recurrence requiring reoperation totaled 2.2% and did not differ between focused parathyroidectomy and open bilateral neck exploration in either intention to treat or final treatment analyses. Complications occurred in 1.2% of focused parathyroidectomy and 3.2% open bilateral neck exploration (P.01).In experienced hands and with a ready-selective approach to conversion, focused parathyroidectomy based on concordant imaging and without intraoperative parathyroid hormone may deliver equivalent cure rates to open bilateral neck exploration with significantly fewer complications. Focused parathyroidectomy without intraoperative parathyroid hormone should therefore be maintained in the endocrine surgeon's armamentarium.

Background Medullary thyroid carcinoma (MTC) can be targeted with tyrosine kinase inhibitors (TKIs). We aimed to report the outcomes of surgically managed MTC and to evaluate the impact of TKI use on patient survival. Methods Consecutive patients treated surgically for MTC from 1986 to 2020 were identified from a prospectively collected database and were compared on the basis of stage at operation and TKI use. The primary outcome was overall survival (OS). Results Among 154 patients with a median age of 52 years, 40% presented with stage I/II disease and 60% presented with advanced (stage III or IV) disease. During a median follow-up of 7.5 years, 21% received TKIs for systemic disease. Those presenting with advanced disease were more likely to receive a TKI (31% vs. 7%), present with tumor invasion of the recurrent laryngeal nerve (RLN; 12% vs. 0%) and undergo reoperation (42% vs. 23%) compared with stage I-II patients. For the 11 patients found to have invasion of the RLN, five had preoperative functional vocal cords. Five-year OS was 84% for advanced disease, and stage IV patients who received TKIs had a median survival of 21 years, versus 15 years for those who did not (p = 0.3). Conclusions Surgery achieves long-term survival for patients with advanced disease, however these patients are at greater risk of requiring RLN resection due to invasion. A significant OS benefit was not seen for TKI use. For patients with local invasion, neoadjuvant TKI therapy may have a role in reducing local morbidity if confirmed to be of benefit in clinical trials.

BACKGROUND Indeterminate thyroid nodules (Bethesda III) are challenging to characterize without diagnostic surgery. Auxiliary strategies including molecular analysis, machine learning models, and ultrasound grading with Thyroid Imaging, Reporting and Data System (TI-RADS) can help to triage accordingly, but further refinement is needed to prevent unnecessary surgeries and increase positive predictive values. DESIGN Retrospective review of 88 patients with Bethesda III nodules who had diagnostic surgery with final pathological diagnosis. MEASUREMENTS Each nodule was retrospectively scored through TI-RADS. Two deep learning models were tested, one previously developed and trained on another data set, mainly containing determinate cases and then validated on our data set while the other one trained and tested on our data set (indeterminate cases). RESULTS The mean TI-RADS score was 3 for benign and 4 for malignant nodules (p = .0022). Radiological high risk (TI-RADS 4,5) and low risk (TI-RADS 2,3) categories were established. The PPV for the high radiological risk category in those with >10 mm nodules was 85% (CI: 70%-93%). The NPV for low radiological risk in patients >60 years (mean age was 100% (CI: 83%-100%). The area under the curve (AUC) value of our novel classifier was 0.75 (CI: 0.62-0.84) and differed significantly from the chance-level (p

We assessed two electronic search tools that screen medical records for documented fractures. Both programs reliably identified patients with any fracture but missed individuals with minimal trauma fracture to different degrees. A hybrid tool combining the methodology of both tools is likely to improve the identification of those with osteoporosis. Most patients who suffer a minimal trauma fracture remain undiagnosed, placing them at high risk of refracture. Case finding can be improved by electronic search tools that screen medical records for documented fractures. Here, we assessed the efficacy of two new programs, AES and XRAIT, in identifying patients with minimal trauma fracture. Each tool was applied to search the electronic medical record and/or radiology reports at two tertiary hospitals in Sydney, Australia, from 1 July to 31 December 2018. Samples of the extracted reports were then manually reviewed to determine the sensitivity of each program in detecting minimal trauma fractures. At the two centers, AES detected 872 and 1364 cases, whereas XRAIT identified 1414 and 2180 patients with fractures, respectively. The true positive rate for “any fracture” was similar for both instruments (77–88%). However, the ability to detect “minimal trauma fractures” differed between programs and centers (53–75% accuracy), with each tool identifying separate subsets of patients. Concordance between both tools was less than half of the combined total number of minimal trauma fractures (43–45%). Considering the total number of minimal trauma fractures detected by both tools combined, AES correctly identified 52–55% of cases while XRAIT identified 88–93% of cases. Both programs reliably identified patients with any fracture but missed individuals with minimal trauma fracture to different degrees. Hybrid tools combining the methodology of XRAIT and AES are likely to improve the identification of patients who require investigation and treatment for osteoporosis.

Objective. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by chronic hypophosphatemia and osteomalacia. We present case of a patient with a protracted clinical course of TIO. TIO profoundly affected every aspect of his life with subsequent profound physical and psychosocial disabilities. Method. The review of a complex clinical presentation, serial laboratory investigations, and imaging modalities of a patient with TIO caused by a mesenchymal tumor. Results. The patient presented with chronic lower back pain, severe bilateral leg weakness, and multiple pathological fractures due to severe osteoporosis. His investigations revealed hypophosphatemia, low 1,25 dihydroxyvitamin D, phosphaturia and normal serum calcium, and parathyroid hormone. Elevated fibroblast growth factor 23 (FGF23) confirmed the diagnosis of TIO and 68Ga-DOTATATE-positron emission tomography/computed tomography (PET/CT) imaging correctly identified a tumor in the left femoral head. His clinical features and biochemical abnormalities promptly recovered after successful surgical resection of the mesenchymal tumor. Conclusion. The present case demonstrated the need to extensively investigate causes of generalized bone pain in patients with hypophosphatemia, as TIO is highly curable. Importantly, 68Ga-DOTATATE PET/CT imaging successfully identified the FGF23 producing tumor, which was undetectable by conventional imaging, favoring its early use in suspected TIO presentation. The present report highlights the importance of timely diagnosis of this complex medical condition, aiming to improve general awareness and enable better clinical outcomes for this rare disorder.

The incidence of papillary thyroid carcinoma (PTC) has increased over recent decades. This apparent epidemic has been attributed to the overdiagnosis of small PTC ≤10 mm in diameter (papillary thyroid microcarcinoma [PTMC]) incidentally detected on imaging for unrelated presentations. Although most PTMCs follow an indolent disease course, there is a small but significant proportion of cases that display more biologically aggressive features such as early metastasis and lymph node involvement. Management of PTMC diagnosed preoperatively should be distinguished from managing those PTMCs incidentally discovered after thyroidectomy. Here, we will focus on the challenge of managing the preoperative patient. Current guidelines recommend against routine biopsy of nodules ≤10 mm, even if they display highly suspicious features on ultrasound; however, it is not known how to identify those PTMCs at higher risk of disease progression. In view of their good prognosis even without surgical resection, active surveillance has emerged as an alternative to operative management for low-risk PTMC without lymph node involvement or distant metastasis. This review aims to summarise active surveillance data for PTMC and identify clinical features that may differentiate the indolent majority from those PTMCs that exhibit early disease progression and metastasis.

Summary Biallelic pathological variants in the thyroid stimulating hormone (TSH) subunit β gene (TSHB) result in isolated TSH deficiency and secondary hypothyroidism, a rare form of central congenital hypothyroidism (CCH), with an estimated incidence of 1 in 65 000 births. It is characterised by low levels of free thyroxine and inappropriately low serum TSH and may therefore be missed on routine neonatal screening for hypothyroidism, which relies on elevated TSH. We describe a patient with CCH who developed recurrence of pituitary hyperplasia and symptomatic hypothyroidism due to poor compliance with thyroxine replacement. She was diagnosed with CCH as a neonate and had previously required trans-sphenoidal hypophysectomy surgery for pituitary hyperplasia associated with threatened chiasmal compression at 17 years of age due to variable adherence to thyroxine replacement. Genetic testing of TSHB identified compound heterozygosity with novel variant c.217A>C, p.(Thr73Pro), and a previously reported variant c.373delT, p.(Cys125Valfs*10). Continued variable adherence to treatment as an adult resulted in recurrence of significant pituitary hyperplasia, which subsequently resolved with improved compliance without the need for additional medications or repeat surgery. This case describes a novel TSHB variant associated with CCH and demonstrates the importance of consistent compliance with thyroxine replacement to treat hypothyroidism and prevent pituitary hyperplasia in central hypothyroidism. Learning points Pathogenic variants in the TSH subunit β gene (TSHB) are rare causes of central congenital hypothyroidism (CCH). c.217A>C, p.(Thr73Pro), is a novel TSHB variant, presented in association with CCH in this case report. Thyroxine replacement is critical to prevent clinical hypothyroidism and pituitary hyperplasia. Pituitary hyperplasia can recur post-surgery if adherence to thyroxine replacement is not maintained. Pituitary hyperplasia can dramatically reverse if compliance with thyroxine replacement is improved to maintain free thyroxine (FT4) levels in the middle-to-upper normal range, without the need for additional medications or surgeries.

Funder: Cancer Research UK Cambridge Cancer Centre, Background: SDHB is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenic SDHB variants in patients with PPGL is essential to the management of patients and relatives due to the increased risk of recurrences, metastases and the emergence of non-PPGL tumours. In this context, the ‘NGS and PPGL (NGSnPPGL) Study Group’ initiated an international effort to collect, annotate and classify SDHB variants and to provide an accurate, expert-curated and freely available SDHB variant database. Methods: A total of 223 distinct SDHB variants from 737 patients were collected worldwide. Using multiple criteria, each variant was first classified according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations and was then manually reviewed by a panel of experts in the field. Results: This multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system (https://databases.lovd.nl/shared/genes/SDHB). Conclusion: This international initiative by a panel of experts allowed us to establish a consensus classification for 223 SDHB variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification of SDHB genetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

Background Prophylactic central lymph node dissection (CLND) in papillary thyroid cancer (PTC) is controversial. We aimed to investigate if prophylactic CLND aids risk stratification and contributes to the decision for postoperative RAI ablation. Methods Patients undergoing thyroidectomy for PTC and prophylactic CLND were identified from an endocrine surgical unit database. Pathology reports where reviewed for number and size of lymph nodes and patients stratified by risk according to the ATA guidelines. Results 426 patients were identified with PTC ≤4 cm and prophylactic CLND. 96 patients (23%) had central lymph node metastasis (CLNM) that qualified them for the intermediate risk group. In 17 patients (4%), the CLNM data led to upgrading independently of other histopathological characteristics. Correcting for multiple variables, CLNM was an independent factor contributing to RAI treatment. Conclusion Prophylactic CLND provides information to aid the selection of RAI ablation independent of primary cancer histology for risk stratification in 4% of patients. This benefit should be carefully balanced with the risk of CLND and patient treatment choice when deciding on management of PTC ≤4 cm.

Currently, monitoring of blood glucose level (BGL) is constrained by the invasive nature of BGL measures. We investigated heart rate variability (HRV) parameters as potential non-invasive markers of BGL. Healthy volunteers (n = 25; aged 27 ± 9 years) uninhibited by regular medications or chronic illness were recruited for this study. BGL and HRV were assessed during fasting (9:00 am), postprandial (12:00 pm), and postabsorptive (3:00 pm) periods using self-monitoring of blood glucose techniques and ten-minute electrocardiogram, respectively. Frequency-domain HRV measures, which estimate contributions of sympathetic and parasympathetic systems to autonomic modulation of the heart, were correlated against BGL data with the following significant (p < 0.05) findings. The change in BGL from fasting to postprandial levels was negatively correlated with fasting low frequency (LF) power and total power (TP). Postprandial BGL was negatively associated with fasting LF and TP, as well as with postprandial LF, high frequency (HF), and TP. The change in BGL from postprandial to postabsorptive levels was positively correlated with fasting LF power, as well as with postprandial LF, HF, and TP. Frequency-domain HRV parameters may be useful in predicting the magnitude and direction of acute fluctuations in BGL, and further research could develop them as non-invasive markers of BGL.

In the 9 years since the publication of our 2011 review of targeted treatment of thyroid cancer with multikinase inhibitors, much has changed in the landscape of this heterogeneous disease. New multikinase and selective inhibitor treatments for medullary thyroid cancer, radioiodine-refractory thyroid cancer and anaplastic thyroid cancer have completed trials and improved progression-free survival. Many physicians are concerned by dose-limiting adverse effects of these drugs and are wary to begin treatment in patients who are systemically well but have marked disease burden, which makes the timing of treatment initiation challenging. Published mechanistic data on tyrosine kinase inhibitors (TKIs) have helped guide our understanding of how to dose effectively with these drugs. A major goal in TKI therapy is to optimize inhibition of oncogenic kinase drivers while maintaining patient quality of life. Real-world data have now been published on how TKIs have fared outside the clinical trial environment. In this Review, we provide a summary of published data on the efficacy of TKIs in clinical practice, to provide clinicians with a more realistic view of how their patients will manage and respond to TKI therapy. Furthermore, we review the data on mechanisms of inhibition, outcomes and adverse effects of TKIs and provide an update on targeted treatment of thyroid cancer, focusing on optimizing the timing of treatment initiation.

Mosaic or somatic EPAS1 mutations are associated with a range of phenotypes including pheochromocytoma and/or paraganglioma (PPGL), polycythemia and somatostatinoma. The pathogenic potential of germline EPAS1 variants however is not well understood. We report a number of germline EPAS1 variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies, EPAS1/HIF-2α p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.

Context Foxe1 is a key thyroid developmental transcription factor. Germline deletion results in athyreosis and congenital hypothyroidism. Some data suggest an ongoing role for maintaining thyroid differentiation. Objective We created a mouse model to directly examine the role of Foxe1 in the adult thyroid. Methods A model of tamoxifen-inducible Cre-mediated ubiquitous deletion of Foxe1 was generated in mice of C57BL/6J background (Foxe1flox/flox/Cre-TAM). Tamoxifen or vehicle was administered to Foxe1flox/flox/Cre mice aged 6-8 weeks. Blood was collected at 4, 12, and 20 weeks, and tissues after 12 or 20 weeks for molecular and histological analyses. Plasma total thyroxine (T4), triiodothyronine, and thyrotropin (TSH) were measured. Transcriptomics was performed using microarray or RNA-seq and validated by reverse transcription quantitative polymerase chain reaction. Results Foxe1 was decreased by approximately 80% in Foxe1flox/flox/Cre-TAM mice and confirmed by immunohistochemistry. Foxe1 deletion was associated with abnormal follicular architecture and smaller follicle size at 12 and 20 weeks. Plasma TSH was elevated in Foxe1flox/flox/Cre-TAM mice as early as 4 weeks and T4 was lower in pooled samples from 12 and 20 weeks. Foxe1 deletion was also associated with an increase in thyroidal mast cells. Transcriptomic analyses found decreased Tpo and Tg and upregulated mast cell markers Mcpt4 and Ctsg in Foxe1flox/flox/Cre-TAM mice. Conclusion Foxe1 deletion in adult mice was associated with disruption in thyroid follicular architecture accompanied by biochemical hypothyroidism, confirming its role in maintenance of thyroid differentiation. An unanticipated finding was an increase in thyroidal mast cells. These data suggest a possible explanation for previous human genetic studies associating alleles in/near FOXE1 with hypothyroidism and/or autoimmune thyroiditis.

COVID-19 has modified the way we practice medicine. For thyroid cancer, there have been several significant impacts. First, the diagnosis has been delayed due to social isolation, reduced access to investigations and staff redeployment. Secondly, treatment planning has needed to take into account the risk to patients and/or staff of nosocomial transmission of the virus. Finally, there are some specific concerns with respect to interactions between the virus, its treatments and cancer. This mini-review aims to address each of these impacts and to provide some guidance and confidence to our patients and colleagues during this challenging time.

Background: Inhibitory antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have antitumor efficacy and are now standard of care in the management of multiple cancer subtypes. However, the use is complicated by the development of autoimmunity, which can occur in multiple organ systems. Thyroiditis is the most common immune-related adverse event. Summary: Immune checkpoint inhibitor (ICI)-associated thyroiditis affects over 10% of treated patients. PD-1 inhibitors are associated with greater risk of thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-CTLA-4 and anti-PD-1 treatment. Onset is typically rapid, within weeks to months and both hyperthyroidism and hypothyroidism can occur. The most frequent pattern of thyroid dysfunction is transient hyperthyroidism with evolution to hypothyroidism over four to six weeks. Most cases are asymptomatic and resolve without dedicated treatment. There is no sex or age predominance, and predictive risk factors have not been reliably identified. Thyroid autoantibodies are variably present and are not clearly related to the risk or progression of thyroid dysfunction following treatment with an ICI. Observational data suggest that development of ICI-associated thyroiditis may predict improved survival. Conclusions: ICI-associated thyroiditis is a distinct clinical entity. Mechanisms underlying etiology remain largely unknown. Awareness among health professionals is important to limit morbidity and avoid unnecessary periods of untreated hypothyroidism.

Summary Lymphocytic hypophysitis is a rare neuroendocrine disease characterised by an autoimmune inflammatory disorder of the pituitary gland. We report a 50-year-old woman who presented with headaches and bilateral sixth cranial nerve palsies. MRI of the pituitary revealed extensive fibrosis involving the sellar and extending into both cavernous sinuses causing bilateral occlusion of the internal carotid arteries (ICA). Transphenoidal biopsy confirmed the diagnosis of infiltrative fibrotic lymphocytic hypophysitis. Symptoms resolved with high dose of oral steroids but relapsed on tapering, requiring several treatments of i.v. pulse steroids over 8 months. Rituximab combined with mycophenolate mofetil was required to achieve long-term symptom relief. Serial MRI pituitary imaging showed stabilisation of her disease without reduction in sellar mass or regression of ICA occlusion. The patient’s brain remained perfused solely by her posterior circulation. This case demonstrates an unusual presentation of a rare disease and highlights a successful steroid-sparing regimen in a refractory setting. Learning points: Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland. In exceptional cases, there is infiltration of the cavernous sinus with subsequent occlusion of the internal carotid arteries. First-line treatment of lymphocytic hypophysitis is high-dose glucocorticoids. Relapse after tapering or discontinuation is common and its use is limited by long-term adverse effects. There is a paucity of data for treatment of refractory lymphocytic hypophysitis. Goals of treatment should include improvement in symptoms, correction of hormonal insufficiencies, reduction in lesion size and prevention of recurrence. Steroid-sparing immunosuppressive drugs such as rituximab and mycophenolate mofetil have been successful in case reports. This therapeutic combination represents a viable alternative treatment for refractory disease.

Assessment of heart rate variability (reflective of the cardiac autonomic nervous system) has shown some predictive power for stress. Further, the predictive power of the distinct patterns of cortical brain activity and - cardiac autonomic interactions are yet to be explored in the context of acute stress, as assessed by an electrocardiogram and electroencephalogram. The present study identified distinct patterns of neural-cardiac autonomic coupling during both resting and acute stress states. In particular, during the stress task, frontal delta waves activity was positively associated with low-frequency heart rate variability and negatively associated with high-frequency heart rate variability. Low high-frequency power is associated with stress and anxiety and reduced vagal control. A positive association between resting high-frequency heart rate variability and frontocentral gamma activity was found, with a direct inverse relationship of low-frequency heart rate variability and gamma wave coupling at rest. During the stress task, low-frequency heart rate variability was positively associated with frontal delta activity. That is, the parasympathetic nervous system is reduced during a stress task, whereas frontal delta wave activity is increased. Our findings suggest an association between cardiac parasympathetic nervous system activity and frontocentral gamma and delta activity at rest and during acute stress. This suggests that parasympathetic activity is decreased during acute stress, and this is coupled with neuronal cortical prefrontal activity. The distinct patterns of neural-cardiac coupling identified in this study provide a unique insight into the dynamic associations between brain and heart function during both resting and acute stress states.

Modification of the cancer-associated chromatin landscape in response to therapeutic DNA damage influences gene expression and contributes to cell fate. The central histone mark H2Bub1 results from addition of a single ubiquitin on lysine 120 of histone H2B and is an important regulator of gene expression. Following treatment with a platinum-based chemotherapeutic, there is a reduction in global levels of H2Bub1 accompanied by an increase in levels of the tumor suppressor p53. Although total H2Bub1 decreases following DNA damage, H2Bub1 is enriched downstream of transcription start sites of specific genes. Gene-specific H2Bub1 enrichment was observed at a defined group of genes that clustered into cancer-related pathways and correlated with increased gene expression. H2Bub1-enriched genes encompassed fifteen p53 target genes including PPM1D, BTG2, PLK2, MDM2, CDKN1A and BBC3, genes related to ERK/MAPK signalling, those participating in nucleotide excision repair including XPC, and genes involved in the immune response and platinum drug resistance including POLH. Enrichment of H2Bub1 at key cancer-related genes may function to regulate gene expression and influence the cellular response to therapeutic DNA damage.

OBJECTIVES Type 3c diabetes mellitus (T3cDM) occurring post pancreatectomy can be challenging to treat due to the frequent combination of decreased circulating levels of insulin and glucagon and concurrent exocrine insufficiency. Relatively, little is known regarding the risk factors for development of T3cDM post pancreatectomy. Our aim was to review the literature and assess what is known of the risk factors for the development of new-onset DM following partial pancreatic resection and where possible determines the incidence, time of onset and the management approach to hyperglycaemia in this context. DESIGN Medline and Embase databases were reviewed using specific keyword criteria. Original manuscripts published in 1990 or later included. Articles with study population

Abuse of androgens and erythropoietin has led to hormones being the most effective and frequent class of ergogenic substances prohibited in elite sports by the World Anti-Doping Agency (WADA). At present, thyroid hormone (TH) abuse is not prohibited, but its prevalence among elite athletes and nonprohibited status remains controversial. A corollary of prohibiting hormones for elite sports is that endocrinologists must be aware of a professional athlete’s risk of disqualification for using prohibited hormones and/or to certify Therapeutic Use Exemptions, which allow individual athletes to use prohibited substances for valid medical indications. This narrative review considers the status of TH within the framework of the WADA Code criteria for prohibiting substances, which requires meeting 2 of 3 equally important criteria of potential performance enhancement, harmfulness to health, and violation of the spirit of sport. In considering the valid clinical uses of TH, the prevalence of TH use among young adults, the reason why some athletes seek to use TH, and the pathophysiology of sought-after and adverse effects of TH abuse, together with the challenges of detecting TH abuse, it can be concluded that, on the basis of present data, prohibition of TH in elite sport is neither justified nor feasible.

Background: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC.Patients and Methods: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival.Results: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival.Conclusion: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk.

[Context]: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. [Objective]: To study whether BRAF V600E affected LNM-associated mortality in PTC. [Design, Setting, and Participants]: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. [Results]: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. [Conclusions]: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance., This work was supported partly by the following funding at the individual participating centers: Polish National Center of Research and Development MILESTONE Project—molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant No. STRATEGMED2/267398/4/ NCBR/2015 (Poland, AC, BJ); Grants No. PID2019-105303RB-I00 (AEI from MICINN), GCB14142311CRES (AECC Foundation), and B2017/BMD-3724 TIRONET2-CM (Spain; PS and GR-E); Grant No. AZV 16-32665A and MH CZ-DRO (Institute of Endocrinology-EU, 00023761) (Czech Republic; BB, VS); NIH/ National Institute on Aging Grant No. 5R03AG042334-02 (LY); and grants from the Qingdao Science and Technology Project for People’s Livelihood No.13-1-3-58-nsh (China; FW) and the Innovative Platform Project of Qingdao No.12-1-2-15-jch (China; YW).

Background: Co-occurrence of TERT (telomerase reverse transcriptase) promoter (TERTp) mutations with BRAF/RAS mutations is associated with significantly more aggressive thyroid cancer. TERTp mutati...

Context Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. Case Series Description Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti–programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti–PD-1–based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)–associated autoantibodies (DAAs) were present in two patients (both of whom had anti–glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy. Conclusion CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure.

Lymphocytic hypophysitis (LYH) is a neuroendocrine disorder characterised by autoimmune inflammation of the pituitary gland with varying degrees of pituitary dysfunction, visual field defects and ocular motility disturbance. The authors report an interesting case of a 50-year-old woman presenting with intermittent bilateral abduction deficits. Neuroimaging and histopathological findings are presented. To the authors’ knowledge, this is the first report of recurrent horizontal binocular diplopia and complete bilateral internal carotid artery occlusion in association with LYH.

© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P

BACKGROUND Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21-year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt. METHODS A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken. RESULTS Thirty-five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki-67 index were strong prognostic indicators for survival. CONCLUSIONS Early stage, complete resection and Ki-67

Context Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. Objective This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. Methods We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. Results A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P Conclusion Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Objective: Our study aimed to analyse temporal trends in radioactive iodine (RAI) treatment for thyroid cancer over the past decade; to analyse key factors associated with clinical decisions in RAI dosing; and to confirm lower activities of RAI for low-risk patients were not associated with an increased risk of recurrence. Methods: Retrospective analysis of 1,323 patients who received RAI at a quaternary centre in Australia between 2008 and 2018 was performed. Prospectively collected data included age, gender, histology, and American Joint Committee on Cancer stage (7th ed). American Thyroid Association risk was calculated retrospectively. Results: The median activities of RAI administered to low-risk patients decreased from 3.85 GBq (104 mCi) in 2008–2016 to 2.0 GBq (54 mCi) in 2017–2018. The principal driver of this change was an increased use of 1 GBq (27 mCi) from 1.3% of prescriptions in 2008–2011 to 18.5% in 2017–2018. In patients assigned as low risk per ATA stratification, lower activities of 1 GBq or 2 GBq (27 mCi or 54 mCi) were not associated with an increased risk of recurrence. In patients assigned to intermediate- or high-risk categories who received RAI as adjuvant therapy, there was no difference in risk of recurrence between 4 GBq (108 mCi) and 6 GBq (162 mCi). Conclusions: Our data demonstrate an evolution of RAI activities consistent with translation of ATA guidelines into clinical practice. Use of lower RAI activities was not associated with an increase in recurrence in low-risk thyroid cancer patients. Our data also suggest lower RAI activities may be as efficacious for adjuvant therapy in intermediate- and high-risk patients.

BACKGROUND The occurrence of distant metastasis (DM) is the most important prognostic factor influencing survival outcomes in differentiated thyroid cancer (DTC). Identifying patients who are likely to develop DM and offering these cases more aggressive surgical approaches and I-131 therapy, is paramount to achieving the best possible outcomes. DM on presentation in DTC are uncommon, with an incidence of 1-9%. However, the incidence of DTC is rising and the disease affects a relatively young cohort of patients. The aims of this study were to investigate predictive factors in the development of DM by comparing a homogenous group of DTC patients with and without DM, and to illustrate the overall and disease-specific survival (DSS) rates of DTC patients presenting with DM. METHODS A matched case-control study of patients with DTC and DM was undertaken. The study group comprised a consecutive series of cases with DM treated in the period 1968-2014. Patients with DM at initial presentation were identified (DTC-DM group). A control group of patients without DM were matched based on age, gender, tumour size and histological subtype. The primary outcome measures were overall and disease-free survival. Secondary outcome measures were lymph node involvement (LNI), extra-thyroidal extension (ETE) of tumour and presence of BRAFV600E mutation identified on immunohistochemistry. RESULTS A total of 2547 patients with DTC were reviewed and of these 83 (3.26%) had DM at initial presentation. At 5 and 10 years, the overall survival rates for DTC-DM patients were 89.6% and 64%, respectively. The 5 and 10 year DSS rates for DTC-DM cases were 90.2% and 67.3%, respectively. When compared to the DTC group, the DTC-DM group had significantly higher rates of ETE (63% vs. 29.5%, P